We have completed our participation in a randomized, multicenter, double blind, placebo-controlled phase III study to evaluate the effect of valaciclovir in preventing the transmission of HSV in heterosexual couples. The seropositive source partner was randomized to receive valaciclovir 500 mg once daily or placebo for 8 months, and the susceptible seronegative partner was monitored monthly for clinical and subclinical (serological) acquisition of HSV. If, at any point, either the source or the susceptible partner presented with clinical symptoms compatible with genital herpes, they were evaluated and treated wit open label valaciclovir. The primary endpoint of the study was the proportion of couples with clinical evidence of a first-episode of genital HSV-2 infection in the susceptible partner. Each endpoint was confirmed by an external Endpoint Committee and required clinical signs/symptoms as well as laboratory confirmation of HSV-2 infection by serology, PCR or culture. Secondary endpoints included the time to clinical symptoms of genital herpes in the susceptible partner, the time to seroconversion in the susceptible partner and the time to first recurrence of HSV in the source partner. After the randomization phase, source partners were eligible to receive 12 months of open label valaciclovir. Patients enrolled in this open-label phase were followed every 3 months for adverse events. The enrollment period was closed on June 30, 2001, with 3996 couples screened, and 1498 couples being randomized in the study. At NIH, we screened a total of 76 couples, with 38 couples being eligible for randomization. Analysis of the study showed that once-daily suppressive therapy with valaciclovir 500 mg reduced transmission of symptomatic genital herpes by 75% versus placebo (0.5 percent vs 2.2 percent). In addition, suppressive therapy with valaciclovir reduced the overall acquisition of the virus by 48% versus placebo (1.9 percent vs. 3.6 percent). There were no differences in the adverse events profile between the two groups. In May 14 2003, the U.S. Food and Drug Administration Advisory Committee unanimously recommended the approval of once-daily suppressive therapy with valaciclovir for the reduction of transmission of genital herpes in otherwise healthy, heterosexual, monogamous couples.